Project Summary Heavy alcohol use frequently co-occurs with smoking, is associated with greatly reduced odds of smoking cessation, and multiplicatively increases the risk of head and neck cancers associated with smoking. Among heavy drinkers, about 40% of smoking lapses occur in situations involving drinking, with heavy drinking further increasing the risk of a smoking lapse beyond the effects of moderate drinking. Laboratory investigations have found that alcohol cues can produce smoking urges, that alcohol use increases craving for cigarettes in a dose dependent fashion, and that alcohol and tobacco each potentiate the rewarding properties of the other. However, no studies have been conducted to date that fully test (a) the unique roles of alcohol stimulus expectancy effects (learned associations) and different doses of alcohol on cigarette smoking, (b) potential mediators of these effects, and (c) potential individual differences that might moderate alcohol- smoking interactions. Towards these ends, two studies are proposed. Study 1 employs a balanced-placebo design for alcohol administration to disaggregate fully alcohol stimulus expectancy effects from pharmacological effects of moderate alcohol doses on three dependent variables: cigarette craving, the incentive salience of smoking, and the ability to resist initiating smoking. Study 2 uses a within-subjects design to examine the effects on these same dependent variables of a 0.8 g/kg dose of alcohol compared to a 0.4 g/kg dose. Both studies will involve 120 heavy social alcohol drinkers who smoke between 10 and 30 cigarettes per day. These studies will be used to test the hypotheses that alcohol's stimulus expectancy and pharmacological effects on smoking are accounted for, in part, by increases in stimulation, accessibility of smoking expectancies, sedation, and discounting of delayed rewards. Furthermore, we hypothesize that alcohol stimulus expectancy effects on smoking will be moderated by alcohol and smoking outcome expectancies, whereas alcohol's pharmacological effects will be moderated by polymorphisms of the DRD4 and OPRM1 receptor genes that have been associated with greater subjective response to alcohol. If successful, these studies can contribute essential information about mechanisms that might account for alcohol's effects on smoking relapse, information that can be used to test potential medication effects in laboratory analogue studies and to develop novel behavioral treatments for the substantial portion of smokers who drink heavily. Given the strong association between drinking and smoking and the interactive effects between alcohol and smoking on head and neck cancer risks, such information can be of significant value to efforts to improve public health. PUBLIC HEALTH RELEVANCE: This project involves two studies in which alcohol is administered to heavy drinking smokers in a laboratory setting to examine how drinking increases craving for cigarettes and decreases the ability to resist smoking. These studies also will examine for whom alcohol consumption is most strongly associated with smoking, focusing on the potential effects of learning and memory, as well as genes. Results of this study will advance understanding of how alcohol use increases the risk of smoking relapse and can inform efforts to increase smoking cessation rates among the relatively high proportion of smokers who drink heavily and are at especially high risk for head, neck, and other cancers.